Olfactory disability represents a danger to the patient resulting from inability to detect hazards such as natural gas and spoiled food and threatens quality of life through the loss of enjoyment of foods and fragrances. Rhinosinusitis is a primary cause of olfactory loss among patients presenting to cliemosensory clinics, and is the most common chronic medical condition in the United States, affecting nearly 33 million people/year. Chronic rhinosinusitis (CR) patients with similar degrees of nasal inflammation may present with normosmia, hyposmia or anosmia, and current therapies are only partially effective. CR may impair olfaction in several ways. Constriction of the airway due to inflammation could alter or impede airflow through the nasal cavity, reducing access of volatile compounds to the sensory receptor cells. Changes in the composition and transport of the watery mucus through which the odorants must diffuse could impair diffusion to or removal from the receptor sites. Proteins secreted by the infiltrating cells of the immune system may directly injure or modulate the function of ORNs or other cells within the neuroepithelium. Fibrosis, gland hyperplasia, keratinization or edema may change the structure of the epithelium or submucosa, impeding axonal outgrowth and preventing successful regeneration of the neuroepithelium. Our limited understanding and the relative importance of these diverse mechanisms and the cellular and molecular processes involved is limiting the development of diagnostic, therapeutic and prognostic tools. This project addresses this need through studies aimed at better understanding the psychophysical (Aim 1), gross anatomical and inflammatory (Aims 1, 2 and collaboration with Project 2) and sensorineural (Aims 3, 4) effects of CR. By comparing data from CR patients with olfactory loss to normosmic CR patients before and after treatment, we will identify features that may be prognostic for olfactory loss/recovery and gain insight into the causes for olfactory loss in CR. We will also develop novel tools for studying airflow dynamics (Aim 1 and collaboration with Project 2) and the effects of CR-associated inflammatory mediators on neurogenesis (Aim 4). Results from this project will enable improved diagnosis and treatment targeting by providing a thorough characterization of the patient population and identifying specific profiles of anatomic, physiologic and sensory characteristics associated with olfactory loss and recovery prospects. Data may also suggest new targets for drug development and will establish a model in vitro system for use in identification and evaluation of novel therapeutic approaches.